RU2184735C2 - Derivatives of spiropiperidine, medicinal agent, method of prophylaxis or treatment - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to novel derivatives of spiropiperidine of the general formula (I)

where R¹ means phenyl group that can be optionally substituted with 1-3 substituents taken among halogen atoms, lower alkyl groups, halogen-lower alkyl groups, lower alkoxy-groups, lower alkoxycarbonyl group, hydroxyl groups, lower aliphatic acylamino-groups, cyano-groups or 5- or 6-membered heterocyclic group comprising 1-3 oxygen, sulfur and/or nitrogen atoms that can be optionally condensed with phenyl group; R² means phenyl group that is substituted with 1-3 fluorine or chlorine atoms; A means carbonyl group; B means an ordinary bond; D means oxygen or sulfur atom; E means C_1-4-alkylene group;

means the group of the formula (II)

where G means C_5-8-alkane ring substituted with hydroxyl group; Ar means phenyl ring; n is a whole number 1 or 2; or their pharmacologically acceptable alts. Invention relates to also a medicinal agent showing an antagonistic effect with respect to NK₁-, NK₂- and NK₃-receptors and containing compound of the formula (I) or its pharmacologically acceptable salt as an effective component and excipient. Proposed compounds can be used for treatment or prophylaxis of disease that can be treated or prevented with agents showing an antagonistic effect with respect to NK₁-, NK₂- and NK₃-receptors by administration of compound of the formula (I) or its pharmacologically acceptable salt in warm-blooded animal in effective dose. EFFECT: new derivatives of spiropiperidine indicated above, valuable pharmacological properties. 12 cl, 3 tbl

Description

[Technical Field]
The invention relates to new derivatives of spiropiperidine, which exhibit antagonistic action against tachykinin receptors (NK ₁ , NK ₂ and NK ₃ ).

[Prior art]
NK ₁ receptors, NK ₂ receptors, and NK ₃ receptors are known to act as tachykinin receptors. A number of compounds are known that exhibit an antagonistic effect on one of these receptors. Recently, compounds that inhibit as many subtypes as possible among the three subtypes have attracted close attention for use in methods for preventing or treating diseases caused by tachykinin. Compounds exhibiting antagonistic activity against both NK ₁ and NK ₂ receptors are being investigated.

For example, compound A shown below is disclosed in EP-776893 as a compound having antagonistic activity with respect to both NK ₁ and NK ₂ receptors. However, it is not reported that this compound exhibits antagonistic activity towards the NK ₃ receptor.

[Сущность изобретения]
Настоящее изобретение относится к:
(1) соединению, представленному формулой (I), или его фармакологически приемлемой соли, сложному эфиру или другому производному

{ где R¹ и R² являются одинаковыми или различными и каждый представляет арильную группу, гетероарильную группу, арильную группу, замещенную от 1 до 3 группами, выбранными из Замещающей Группы А, или гетероарильную группу, замещенную от 1 до 3 группами, выбранными из Замещающей Группы А,
А представляет метиленовую группу, карбонильную группу или сульфонильную группу,
В представляет одинарную связь, С_1-4алкиленовую группу или С_2-4алкениленовую группу,
D представляет атом кислорода или атом серы,
Е представляет С_1-4алкиленовую группу или С_2-4алкениленовую группу,

где G представляет С_5-8циклоалкеновый цикл, С_5-8циклоалкановый цикл, замещенный 1 или 2 группами, выбранными из Замещающей Группы В, или циклоалкеновый цикл, замещенный 1 или 2 группами, выбранными из Замещающей Группы В,
Аr представляет арильный цикл, гетероарильный цикл, арильный цикл, замещенный от 1 до 3 группами, выбранными из Замещающей Группы А, или гетероарильный цикл, замещенный от 1 до 3 группами, выбранными из Замещающей Группы А,
R³ представляет низшую алкильную группу, и
n представляет целое число от 1 до 3;
при условии, что G не включает группу, замещенную только оксогруппой};
[Замещающая Группа А]
атомы галогена, низшие алкильные группы, галогеннизшие алкильные группы, низшие алкоксигруппы, низшие алкоксикарбонильные группы, карбоксильные группы, гидроксильные группы, низшие алифатические ацильные группы, низшие алифатические ациламиногруппы, аминогруппы и цианогруппы;
[Замещающая Группа В]
оксогруппы, гидроксильные группы, карбоксильные группы или тиольные группы; и, в качестве заместителей атома азота, низшие алкильные, арильные, аралкильные, низшие алифатические ацильные и низшие алкансульфонильные группы, каждая из которых может быть замещена группой, выбранной из Замещающей Группы А.

[Summary of invention]
The present invention relates to:
(1) a compound represented by formula (I), or a pharmacologically acceptable salt, ester or other derivative thereof

{where R ¹ and R ² are the same or different and each represents an aryl group, a heteroaryl group, an aryl group substituted by 1 to 3 groups selected from Substitution Group A, or a heteroaryl group substituted by 1 to 3 groups selected from Substitution Group A
A represents a methylene group, a carbonyl group or a sulfonyl group,
B represents a single bond, a C _1-4 alkylene group or a C _2-4 alkenylene group,
D represents an oxygen atom or a sulfur atom,
E represents a C _1-4 alkylene group or a C _2-4 alkenylene group,

where G represents a C _5-8 cycloalkene cycle, a C _5-8 cycloalkane cycle substituted by 1 or 2 groups selected from Substitution Group B, or a cycloalkene cycle substituted by 1 or 2 groups selected from Substitution Group B,
Ar represents an aryl ring, a heteroaryl ring, an aryl ring substituted by 1 to 3 groups selected from Substitution Group A, or a heteroaryl ring substituted by 1 to 3 groups selected from Substitution Group A,
R ³ represents a lower alkyl group, and
n represents an integer from 1 to 3;
provided that G does not include a group substituted only by an oxo group};
[Substitute Group A]
halogen atoms, lower alkyl groups, halogen lower alkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups, carboxyl groups, hydroxyl groups, lower aliphatic acyl groups, lower aliphatic acylamino groups, amino groups and cyano groups;
[Substitute Group B]
oxo groups, hydroxyl groups, carboxyl groups or thiol groups; and, as substituents on the nitrogen atom, lower alkyl, aryl, aralkyl, lower aliphatic acyl and lower alkanesulfonyl groups, each of which may be substituted by a group selected from Substitution Group A.

(12) соединения, где G представляет циклопентановый или циклопентеновый цикл, замещенный одной или двумя группами, выбранными из Замещающей Группы В,
(13) соединения, где G представляет циклопентановый или циклопентеновый цикл, замещенный гидроксигруппой,
(14) соединения, где п представляет 1 или 2, и
(15) соединения, где п представляет 2;
и их фармакологически приемлемые соли, сложные эфиры или другие производные.Among them, preferred compounds are:
(2) compounds wherein R ¹ represents an aryl group, a heteroaryl group or an aryl group substituted by 1 to 3 groups selected from Substitution Group A,
(3) compounds wherein R ¹ represents an aryl group or an aryl group substituted by 1 to 3 groups selected from Substitution Group A ¹ as defined below,
(4) compounds wherein R ² represents an aryl group or an aryl group substituted by 1 to 3 groups selected from Substitution Group A,
(5) compounds wherein R ² represents an aryl group substituted by at least one group selected from Substitution Group A,
(6) compounds wherein A represents a carbonyl group,
(7) compounds wherein B is a single bond,
(8) compounds where D represents an oxygen atom,
(9) compounds wherein E represents a C _1-4 alkylene group,
(10) compounds wherein E represents a C _2-3 alkylene group,
(11) compounds where

(12) compounds wherein G represents a cyclopentane or cyclopentene ring substituted with one or two groups selected from Substitution Group B,
(13) compounds wherein G represents a cyclopentane or cyclopentene ring substituted with a hydroxy group,
(14) compounds wherein n is 1 or 2, and
(15) compounds wherein n is 2;
and their pharmacologically acceptable salts, esters or other derivatives.

[Substitution Group A ¹ ]
lower alkyl groups, halogen-lower alkyl groups and lower alkoxy groups.

 Of the above compounds, compounds that include a combination of factors selected from eight groups consisting of (2) and (3); (4) and (5); (6); (7); (8); (9) and (10); from (11) to (13); and (14) and (15) are also preferred.

(16) More preferred compounds are:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(1H-indene-1,4'-piperidine ],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4'-piperidine ],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4'-piperidine ], and
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(1H-indene-1,4'-piperidine],
and their pharmacologically acceptable salts, esters and other derivatives.

(17) Most preferred are compounds:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine] and
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine],
and their pharmacologically acceptable salts, esters and other derivatives.

 The novel drug of the present invention includes, as an effective ingredient, a compound selected from any one of the compounds described above in (1) to (17), or a pharmacologically acceptable salt, ester or other derivative thereof, and can be used especially as a prophylactic or medicines for asthma and / or bronchitis, rhinitis, allergies and urinary incontinence.

In the formula (I), examples of the “aryl group” in the definitions of R ¹ and R ² , the aryl group of “n an aryl group substituted by 1 to 3 groups selected from Substitution Group A” in the definitions of R ¹ and R ² , and “aryl group ““ an aryl group which may be substituted with a group selected from Substitution Group A ”in the definition of“ Substitution Group B ”includes C _5-8 aromatic hydrocarbon groups such as phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl, of which phenyl groups are preferred.

In this case, the above “aryl group” may form a fused nucleus with a C _3-10 cycloalkyl group, and examples of such groups include 5-indanyl groups.

The "heteroaryl group" in the definitions of R ¹ and R ² and the "heteroaryl group" of the "heteroaryl group substituted by 1 to 3 groups selected from Substitution Group A" in the definitions of R ¹ and R ² means a 5-7 membered aromatic heterocyclic group containing from 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups. Among these 5-7 membered aromatic heterocyclic groups, the most preferred are groups each of which contains at least one nitrogen atom and, in addition to it, may additionally contain an oxygen atom or a sulfur atom. Examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl groups, of which imidazole groups are more preferred. oxazolyl, pyrazinyl and thiazolyl.

 In addition, the above-described “heteroaryl group” may form a fused nucleus with another cyclic group. Examples of such groups include indolyl, benzofuryl, benzothienyl, benzoxazolyl, benzoimidazolyl, isoquinolyl, quinolyl and quinoxalil.

Examples of a "lower alkyl group" in the definition of R ³ , [Substitution Group A] and [Substitution Group A '] and a "lower alkyl group" of a "lower alkyl group which may be substituted by a group selected from Substitution Group A" in the definition of [ Substitution Group B] includes C _1-6 straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-di etilbutil, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups, of which _C1-4 alkyl groups are straight- or branched-chain are preferred.

Examples of the “C _1-4 alkylene group” in Definitions B and E include straight or branched chain C _1-4 alkylene groups such as methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene and 3 methyl trimethylene.

With respect to B, linear or branched chain C _1-3 alkylene groups are preferred.

With respect to E, C _1-3 straight or branched chain alkylene groups are preferred, of which ethylene and trimethylene groups are more preferred, and an ethylene group is most preferred.

Examples of the “C _2-4 alkenylene group” in Definitions B and E include C _2-4 straight or branched chain alkenylene groups such as ethenylene, 2-propenylene, 1-methyl-2-propenylene, 2-methyl-2-propenylene , 2-ethyl-2-propenylene and 2-butenylene, of which ethenylene, 2-propenylene and 3-butenylene groups are preferred, and ethenylene and 2-propenylene groups are more preferred.

Examples of “C _5-8 cycloalkene cycle” and “C _5-8 cycloalkene cycle”, “C _5-8 cycloalkene cycle substituted with 1 or 2 groups selected from Substitution Group B” in definition G include cyclopentene, cyclohexene, cycloheptene and cyclooctene cycles, of which a “C _5-6 cycloalkene cycle” is preferred, and cyclopentene cycles are more preferred.

Examples of “C _5-8 cycloalkane ring” “C _5-8 cycloalkane ring substituted with 1 or 2 groups selected from Substitution Group B” representing G include cyclopentane, cyclohexane, cycloheptane and cyclooctane rings, of which “C _5-6 "cycloalkane ring" is preferred, and cyclopentane rings are more preferred.

Examples of the “aryl ring” and “aryl ring” of the “aryl ring substituted by 1 to 3 groups selected from Substitution Group A” in the definition of Ar include C _6-14 aromatic hydrocarbon rings such as benzene, indene, naphthalene, phenanthrene and anthracene cycles, of which benzene cycles are preferred.

 The “heteroaryl ring” and the “heteroaryl ring” of the “heteroaryl ring substituted with 1 to 3 groups selected from Substitution Group A”, each in the definition of Ar, denote a 5-7 membered aromatic heterocycle containing from 1 to 3 sulfur atoms, atoms oxygen and / or nitrogen atoms. Examples include cycles such as furan, thiophene, pyrrole, azepine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine and pyrazine. Among these 5 to 7 membered aromatic heterocycles, preferred are rings which contain at least one nitrogen atom and which may also contain an oxygen atom or a sulfur atom, and examples include cycles such as pyrrole, azepine, pyrazole, imidazole, oxazole , isoxazole, thiazole, isothiazole, 1,2,3-oxadiazole, triazole, tetrazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine, of which the cycles of pyridine, imidazole, oxazole, pyrazine and thiazole are more preferred.

включают 2-гидроксииндан-1,1-диил (в частности, 2S-гидроксииндан-1,1-диил), 3-гидроксииндан-1,1-диил, 2,3-дигидроксииндан-1,1-диил и инден-1,1-диил.Accordingly, examples of the group represented by the following formula:

include 2-hydroxyindan-1,1-diyl (in particular 2S-hydroxyindan-1,1-diyl), 3-hydroxyindan-1,1-diyl, 2,3-dihydroxyindan-1,1-diyl and inden-1 , 1-diyl.

 "Halogen atoms" in the definition of [Substitution Group A] include fluorine, chlorine, bromine and iodine atoms, of which fluorine and chlorine atoms are preferred.

 "Halogen-lower alkyl groups" in the definition of [Substitution Group A] and [Substitution Group A '] refers to groups in which the above-described "halogen atom" is attached to a "lower alkyl group". Examples include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl and 2,2-dibromethyl, of which trifluoromethyl, 2-bromoethyl, 2-chloroethyl and 2-fluoroethyl are preferred.

"Lower alkoxy groups" in the definitions of [Substitution Group A] and [Substitution Group A '] and "lower alkoxy groups" of a "lower alkoxycarbonyl group" in the definition of [Substitution Group A] mean a group in which the above "lower alkyl group" is attached to an oxygen atom . Examples include straight or branched chain C _1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy , n-hexoyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3 -dimethylbutoxy, of which C _1-4 straight or branched chain alkoxy groups are preferred.

Each of the "lower aliphatic acyl groups", "lower aliphatic acyl groups", "lower aliphatic acylamino groups" in the definition of [Substitution Group A] means C _2-7 aliphatic acyl groups. Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl and isovalery groups, of which acetyl and propionyl groups are preferred.

R ¹ is preferably an aryl group, a heteroaryl group or an aryl group substituted with 1-3 groups selected from Substitution Group A; more preferably is an aryl group or an aryl group substituted by 1-3 groups selected from Substitution Group A; even more preferably is an aryl group substituted by 1-3 groups selected from Substitution Group A ′; and most preferred is an aryl group substituted with 1 to 3 lower alkoxy groups.

R ² is preferably an aryl group substituted by 1 to 3 groups selected from Substitution Group A; more preferably is an aryl group substituted by 1-3 groups selected from Substitution Group A; even more preferably is an aryl group substituted by 1-3 halogen atoms; and, most preferably, is a phenyl group substituted by 1-3 halogen atoms.

Так как соединения (I) настоящего изобретения могут образовывать соль, "их фармакологически приемлемые соли" представляют такую соль.The following formula preferably represents a group in which a carbon atom adjacent to the carbon atom forming the spiro bond between the group G and the piperidine ring and its adjacent carbon atom form part of the cyclic group Ar, as well as part of the cyclic group G

Since the compounds (I) of the present invention can form a salt, "their pharmacologically acceptable salts" represent such a salt.

 Preferred examples of salts comprising the compounds (I) of the invention and an acid include inorganic acid salts such as hydrohalic acid salts (e.g. hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), nitrates, perchlorates, sulfates, phosphates and the like; salts of organic acids such as lower alkanesulfonates (e.g. methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), aryl sulfonates (e.g. benzenesulfonate, p-toluenesulfonate, etc.), salts of acetic acid, malonic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate and the like; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, aspartate and the like; of which salts of hydrohalic acid and salts of organic acid are more preferred, salts of halogen acid are even more preferred, and hydrochloride is most preferred.

 On the other hand, preferred examples of the salt formed by the compound (I) of the invention and the base include metal salts, for example alkali metal salts such as potassium salts, sodium and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts aluminum and iron salts; amine salts, for example inorganic salts, such as ammonium salts, and organic salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenyl glycine alkyl ester salts, ethylene diamine salts, N-methyl glucamine salts, guanidine salts, diethyl salts , triethylamine salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts, chloroprocain salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetraethiammonium salts and tris (hydroxymethyl) aminomethane salts; amino acid salts such as salts of glycine, lysine, arginine, ornithine, glutamic acid and aspartic acid salts.

Since the compounds (I) of this invention can be converted to the corresponding quaternary salts by modifying the nitrogen atom of the piperidine group in the molecule with the group R ³ , the salts between such a cationic compound and the anion (there are no particular restrictions on the anion, provided that it serves as anion, and examples include halogen anions such as chloride anion and iodide anion) are also encompassed by the present invention.

 In addition, the compounds (I) of the present invention absorb water and contain this absorbed water added to them, or become hydrates when they are left to stand in the air. Such salts are also encompassed by the present invention.

 "Ester or other derivative thereof" means a compound in which a functional group (for example, a hydroxy group, a carboxy group or an amino group) is modified by a protecting group or the like, and which can be converted to the compound (I) of the present invention after its introduction into a living organism. Whether a compound is such a derivative can be established by administering it to an experimental animal, such as a rat or mouse, intravenously, examining the animal body fluid after administration and detection of the parent compound or its pharmaceutically acceptable salt.

 Since the compounds (I) of the present invention can be converted into the corresponding esters, “esters” means such esters. Examples of esters include "hydroxyl group esters" and "carboxyl group esters". This means an ester in which the ester residue is a “traditional protecting group”, or “a protecting group that can be removed in vivo by a biological method such as hydrolysis”.

 “Traditional protecting group” means a protecting group that can be removed chemically, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

 Preferred examples of the “conventional protecting group” for the “hydroxyl ester group” include the above “lower aliphatic acyl groups”; the above "aromatic acyl groups"; "tetrahydropyranyl or tetrahydrothiopyranyl groups" such as tetrahydropyranyl-2-yl, 3-bromo-tetrahydropyranyl-2-yl, 4-methoxytetrahydropyranyl-4-yl, tetrahydrothiopyranyl-2-yl and 4-methoxytetrahydrothiopyranyl-4; "tetrahydrofuranyl or tetrahydrothiofuranyl groups" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; "silyl groups", for example, tri (lower alkyl) silyl groups such as trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, tert-butylsilyl, methyldiisopropylsilyl, methyl di-tert-butylsilyl and triisopropylsilyl and three (lower alkyl) silyl groups 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl; “alkoxymethyl groups”, for example lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl, lower alkoxymethyl groups substituted with lower alkoxymethyl groups, and (halogen lower alkoxy) methyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; “substituted ethyl groups”, for example, ethyl groups substituted by a lower alkoxy group such as 1-ethoxyethyl and 1- (isopropoxy) ethyl and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; “aralkyl groups”, for example lower alkyl groups substituted with 1-3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl group, and lower alkyl groups, each of which substituted by 1 to 3 aryl groups having aryl substituted by lower alkyl, halogen (lower alkyl), lower alkoxy, nitro, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5- trimethylbenzyl, 3,5-di (trifluoromethyl) benzyl, 4-methoxybenzyl, 4-methoxyphenyl diphenyl Teal, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; and the above "lower alkoxycarbonyl groups".

 Preferred examples of a “conventional protecting group” for an ester of a carboxyl group include the above “lower alkyl groups”; lower alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2- ethyl 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3- pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl; lower alkynyl groups such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3- butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentinyl, 1-methyl-3-pentinyl, 2-methyl-3-pentinyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl; the above "halogen-lower alkyl groups"; hydroxy lower alkyl groups such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl; "lower aliphatic acyl" - "lower alkyl groups" such as acetylmethyl groups; the above "aralkyl groups" and the above "silyl groups".

 "Protecting groups that can be cleaved in vivo by a biological method such as hydrolysis" means a protecting group that is removed in vivo by a biological method, such as hydrolysis, and forms the free acid or its salt. Whether the ester is such a derivative can be established by intravenously administering this ester to an experimental animal such as a rat or mouse, examining the body fluid of the animal after administration and detecting the parent compound or a pharmacologically acceptable salt thereof.

 Preferred examples of "protecting groups that can be removed in vivo by biological means, such as hydrolysis" for a "hydroxyl ester" include 1- (acyloxy) "lower alkyl groups", for example 1 - ("lower aliphatic acyl" oxy), "lower alkyl groups" such as formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-acetoxyethyl, 1-acetoxyethyl, 1-acetoxyethyl, 1-hydroxy-ethyl-1-ethyl-ethyl-1-ethyl-ethyl-1-ethyl-ethyl-1-ethyl-ethyl-ethyl aloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl, 1-isovaleryloxypropyl 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl, 1 - ("cycloalkylcarbonyloxy) -alkylalkyloxymethyl groups cyclohexylcarbon loksimetil, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-tsiklopentilkarboniloksipropil, tsiklogeksilkarboniloksipropil-1, 1-tsiklopentilkarboniloksibutil tsiklogeksilkarboniloksibutil and 1, and 1 - ( "aromatic acyl" oxy) "lower alkyl groups" such as benzoyloxymethyl groups; (Lower alkoxycarbonyloxy) alkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentiloksikarboniloksimetil, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- ( propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy ) ethyl, 1-tert-butoxycarbonyloxy) ethyl, 1-pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1-cyclohexyloxycarbonyloxy) propyl, 1- ( 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 2- (methoxycarbonyloxy) ethyl, 2-ethoxycarbonyloxy) ethyl, 2- (propoxycarbonyloxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2 - (isobutoxycarbonyloxy) ethyl, 2- (pentyloxycarbonyloxy) ethyl, 2- (hexyloxy rbonyloxy) ethyl, 1-methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl propyl, 1- (hexyloxycarbonyloxy) propyl, 1-methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isoxybutyloxybutoxy, butyl 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hex strength and 1- (ethoxycarbonyloxy) hexyl; and oxodioxolenylmethyl groups such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2 -oxy-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolene -4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; “phthalidyl groups” such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; the above-described "lower aliphatic acyl groups", the above-described "aromatic acyl groups"; "salt of the semi-ester residue of succinic acid"; "phosphate salt residues"; "ester-forming residues similar to amino acids"; carbamoyl groups; carbamoyl groups substituted with 1 or 2 lower alkyl groups; and “1- (acyloxy) alkylcarbonyl groups” such as pivaloyloxymethyloxycarbonyl, of which “carbonyloxyalkyl groups” are preferred.

 Preferred examples of a “protecting group that can be removed in vivo by biological means such as hydrolysis” for “carboxy ester” include “alkoxidized alkyl groups”, for example (lower alkoxy) (lower alkyl) groups such as methoxyethyl, 1-ethoxyethyl , 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl and tert-butoxymethyl, (lower alkoxy) lower alkyl groups substituted with lower alkoxy, such as 2-meth hydroxyethoxymethyl, aryl hydroxy lower alkyl groups such as phenoxymethyl groups, and (halogenated lower alkoxy) (lower alkyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl groups; "" lower alkoxy "carbonyl << lower alkyl groups >>>> such as methoxycarbonylmethyl groups; << cyano >> lower alkyl groups >>>> such as cyanomethyl and 2-cyanoethyl; <<<< lower alkyl >> thiomethyl groups> > such as methylthiomethyl and ethylthiomethyl; "" aryl "thiomethyl groups" such as phenylthiomethyl and naphthylthiomethyl; “lower alkyl” sulfonyl “lower alkyl groups” which may be substituted with halogen, such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl groups; “aryl” sulfonyl “lower alkyl groups” such as 2-benzylsulfonylethyl and 2-toluenesulfonylethyl ; the above-described "1- (acyloxy)" lower alkyl groups ""; the above-described "phthalidyl groups"; the above-described "aryl groups"; the above-described "lower alkyl groups"; "carboxyalkyl groups" such as carboxymethyl; and "amide-forming amino acid residues", such as phenylalanine.

 When the compounds (I) of the present invention contain an amino and / or carboxyl group, they can be converted into derivatives other than the above-described "pharmacologically acceptable salts" and "their esters". “Other derivatives” means such derivatives. Examples of such derivatives include amide derivatives.

 Compounds (I) of the present invention contain an asymmetric carbon atom in their molecule, and stereoisomers whose asymmetric atom has an R or S configuration are present. The stereoisomers and their mixture in any respect are also included in the present invention.

[Embodiments of the invention]
Derivatives of spiropiperidine of the present invention can be obtained by the following method.

В вышеприведенной схеме реакции,
R¹, R², А, В, D, Е, М и n принимают те же самые вышеописанные значения.[Method A]

In the above reaction scheme,
R ¹ , R ² , A, B, D, E, M and n take the same values described above.

 Y 'may be any group capable of removal, like a nucleophilic residue, and is not particularly limited. Preferred examples of such groups include halogen atoms such as chlorine, bromine and iodine; trihalomethoxy groups such as trichloromethoxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy groups; (halo lower alkyl) sulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups; and arylsulfonyloxy groups such as benzenesulfoyloxy, p-toluenesulfonyloxy and p-nitrophenylsulfonyloxy groups, of which halogen atoms and lower alkanesulfonyloxy groups are even more preferred.

 Step A1 is a step for preparing a compound (I) of the present invention by reacting a compound (II) with a compound (III) in a solvent in the presence of a base.

 The nature of the solvent used is not particularly limited, provided that it does not adversely affect the reaction and is capable of at least to some extent dissolving the starting materials.

 Preferred examples include aliphatic hydrocarbons such as hexane, heptane, naphtha and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphotriamide; and sulfoxides, such as dimethyl sulfoxide and sulfolane, of which amides, ethers and nitriles are preferred, and amides are most preferred.

 There are no particular restrictions on the nature of the base used, provided that the base is used in ordinary reactions. Preferred examples include combinations of metal iodide (e.g., potassium iodide) and an inorganic base, such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate or lithium carbonate), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate), alkali metal hydride (e.g. lithium hydride, sodium hydride or potassium hydride), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide) or alkali metal fluoride alla (e.g. sodium fluoride or potassium fluoride); or an organic base such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert -butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2 ] octane (DABCO) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), of which a combination of metal iodide and an inorganic base is more preferred, and a combination of iodine is most preferred and metal and alkali metal hydrogencarbonate.

The reaction temperature ranges from 0 to 150 ^o C, from 20 to 120 ^o C.

 Although the reaction time depends mainly on the temperature and nature of the feed, reaction reagents and solvent used, it usually ranges from 30 minutes to 48 hours, from 1 to 12 hours.

 The compound of formula (I), where a carbon atom, which is a ring atom of group G and which is not adjacent to the piperidine ring and has a hydroxyl group, can be obtained by reduction of the corresponding ketone derivative, which is obtained in accordance with the above method A.

 The nature of the solvent used is not particularly limited, provided that it does not adversely affect the reaction and is capable of at least to some extent dissolving the starting materials. Preferred examples include alcohols, such as methanol or ethanol; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, of which alcohols are preferred, and ethanol is most preferred.

 There are no particular restrictions on the nature of the reducing agent used, provided that it is usually used as a reducing agent. Preferred examples include hydride reagents, such as alkali metal borohydrides (e.g., sodium borohydride or lithium borohydride), aluminum hydride compounds (e.g., lithium aluminum hydride or lithium triethoxyaluminum hydride), sodium tellurium hydride, and organic aluminohydride reducing agents [e.g., diisobutylaluminum hydride ) sodium aluminum dihydride], of which alkali metal borohydrides and organic aluminum hydride reducing agents are most preferred, most preferred itelnymi are alkali metal borohydrides.

The reaction temperature ranges from -78 to 50 ^o C, from -20 to 20 ^o C.

 The reaction time depends mainly on the temperature and nature of the raw materials, reaction reagents and solvent used. Usually it ranges from 5 minutes to 24 hours, from 10 minutes to 2 hours.

 After completion of the corresponding reactions, the compounds obtained by the corresponding reactions can be isolated from the reaction mixture in the usual manner.

 For example, the reaction mixture is neutralized accordingly and, after removal of the insoluble matter, if any, by filtration, an organic solvent immiscible with water (for example, ethyl acetate) is added. After washing with water and the like, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate and the like. Then the solvent is distilled off to obtain the target compound.

 The desired compound obtained, if desired, is isolated and purified by conventional methods, such as crystallization and reprecipitation, or by methods that are commonly used for the isolation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, aluminum or magnesium silica gel, florisil ; a method using synthetic adsorbents, for example separation column chromatography using Sephadex LH-20 (manufactured by Pharmacia Co.), Amberlite XAD-11 (manufactured by Rohm & Haas Co.), Diaion HP-20 (manufactured by Mitsubishi Kasei Co., Ltd.) ; a method using ion exchange chromatography; or normal / reverse phase liquid chromatography (high performance liquid chromatography using silica gel or alkylated silica gel; or in combination with a suitable solvent.

 In this case, the feed is commercially available or can be easily obtained by known methods. For example, a compound of formula (II) can be obtained by the method disclosed in EP-776893 and the like, while a compound of formula (III) can be obtained by a method well known in the art (see, for example, US Pat. No. 5,578,593) and like him.

The new spiro pyridine derivatives of the present invention have excellent antagonism against tachykinin, excellent antagonistic activity against NK ₁ , NK ₂ and NK ₃ receptors, excellent oral absorption and less toxicity, which makes them useful as a medicine. Examples of diseases for which this drug is useful as a prophylactic or therapeutic agent include diseases of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; sleep apnea syndrome; neurodegenerative diseases such as dementia caused by AIDS, senile dementia,
Alzheimer's disease, Down syndrome, demyelination, atrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases, such as chronic abstructive pulmonary disease, bronchitis, pneumonia, bronchostenosis, asthma and cough; inflammatory diseases such as digestive tract inflammation (IBD), psoriasis, fibrosis, epiphase osteomyelitis, osteoarthritis and rheumatoid arthritis; allergic diseases such as rhinitis and eczema; hypersensitivity disease, such as hypersensitivity to grapes; ophthalmic diseases such as conjunctivitis, spring conjunctivitis, spring catarrh of the upper respiratory tract, destruction of the blood-ophthalmic barrier in case of various inflammatory diseases of the eye, increased intraocular pressure and myosis; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addiction, such as alcohol addiction; somatic diseases caused by stress; dystrophy of the sympathetic reflex, such as carpal and shoulder syndrome; dysthymia; an unwanted immune reaction, including transplant rejection, an immune-related disease, including lupus erythematosus and immune suppression; digestive diseases, including diseases caused by disorders in the nerves that regulate organs, colitis, ulcerative colitis and Crohn's disease, vomiting, including vomiting caused by the harmful effects of x-rays and chemotherapy, poisons, toxins, pregnancy, upset vestibular apparatus, postoperative suffering, gastrointestinal - intestinal occlusion, reduced movement along the gastrointestinal tract, visceral pain, migraine, increased arterial pressure, intracranial pressure, or the management of various drugs; functional diseases of the bladder, such as cystitis or urinary incontinence; collagen-induced zosinophilia, scleroderma, or Fasciola hepatica (hepatic hepatic) infection; diseases caused by abnormal blood flow caused by the expansion or narrowing of blood vessels, such as angina pectoris, migraine and Raynaud's disease; and painful nocireceptor diseases such as migraine, cephalalgia, and odontalgia.

 Compounds (I) of the present invention can be administered orally, for example, in the form of tablets, capsules, granules, powders or syrups, or administered parenterally, for example, in the form of injection preparations or suppositories. Such preparations can be prepared in a substantially known manner using additives such as excipients [for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch; cellulose derivatives such as crystalline cellulose, unsubstituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally cross-linked sodium carboxymethyl cellulose; gum arabic; dextrin; organic excipients such as pollulan; flint derivatives, such as light anhydrous silicic acid, synthetic aluminosilicate or magnesium aluminate metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; inorganic excipients such as sulfates (eg, calcium sulfate)]; lubricants [eg metal stearates such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silicon dioxide; waxes such as beeswax and spermaceti; boric acid; adipic acid ;, sulfates, such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicate hydrate; and the above starch derivatives]; binders [for example, polyvinylpyrrolidone, macrogol or the same compounds as the above excipients; disintegrants, for example the same compounds as the above excipients and chemically modified starch celluloses, such as croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone]; stabilizers [for example, para-hydroxybenzoates such as methyl-para-aminobenzoic acid (methylparaben) and propyl-para-aminobenzoic acid (propylparaben); alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonide chloride; phenols such as phenol and cresol; trimecosol; dehydroacetic acid; and sorbic acid]; drug modifiers [eg, commonly used sweeteners, acidic agents or flavorings]; and diluents according to known methods.

 The dose varies depending on the severity of the disease, age, route of administration, and the like. For example, in the case of oral administration, it is favorable if the compound of the present invention is administered once to several times a day at a dose of from 0.01 mg / kg body weight (0.1 mg / kg body weight, the preferred lower limit) to 100 mg / kg body weight (50 mg / kg body weight, upper limit preferred) depending on the severity of the disease. In the case of intravenous administration, it is favorable if the compound of the present invention is administered from one to several times a day at a dose of from 0.01 mg / kg body weight (0.05 mg / kg body weight, the preferred lower limit) to 100 mg / kg body weight (50 mg / kg body weight, upper limit preferred) depending on the severity of the disease.

[Best Mode for Carrying Out the Invention]
The present invention will now be described in further detail with examples, examples of compositions, and test examples. However, they should not be taken to limit the scope of the present invention.

[Examples]
[Example 1]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine] (Compound 138 described below)
200 mg (0.37 mmol) of 2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethanol methanesulfonate are suspended in 4 ml of anhydrous dimethylformamide, 96 mg (0.40 mmol) of spiro [(2-hydroxy) indan-1,4'-piperidine] hydrochloride obtained in Reference Example 3, 92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) potassium iodide, followed by heating at 80 ^o C for 8 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under vacuum. The residue was purified by thin-layer chromatography on silica gel (solvent; methylene chloride: methanol = 10: 1) to obtain 175 mg (73%) of the title compound as white crystals.

[α] _D + 11.8 ^° (c = 0.56, chloroform).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm: 7.16-7.67 (7H, m), 6.52 (2H, s), 4.40 (1H, s), 3.85 (9H, s), 3.37-4.04 (6H, m), 3.27 (1H, dd, J = 16.7, 5.3 Hz), 2.82 (1H, d, J = 16 , 7 Hz), 2.62-2.88 (2H, m), 1.49-2.40 (10H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3432, 2934, 1634, 1584
Mass Spectrometric Analysis (FAB) m / e: 655 (M + H) ⁺ .

Elemental analysis (% based on C ₃₅ H ₄₀ N ₂ O ₆ Cl ₂ • 0.5H ₂ O)
Calculated: C 63.25, H 6.22, N 4.21, Cl 10.67.

 Found: C, 63.24; H, 6.37; N, 4.14; Cl, 10.41.

[Example 2]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine] (Compound 106 described below)
[Example 2a]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine]
200 mg (0.37 mmol) of 2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethanolmethanesulfonate, 95 mg, are suspended in 4 ml of anhydrous dimethylformamide. (0.40 mmol) spiro [(3-hydroxy) indan-1,4'-piperidine] hydrochloride obtained in Reference Example 5, 92 mg (1.10 mmol) of sodium bicarbonate and 91 mg (0.55 mmol) of iodide potassium, followed by heating at 80 ^o C for 8 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under vacuum. The residue was purified by silica gel thin-layer chromatography (solvent; methylene chloride: methanol = 10: 1) to obtain 167 mg (70%) of the title compound as white crystals.

[α] _D + 11.8 ^° (c = 0.53, chloroform).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl ₃ ) δ, ppm: 7.29-7.78 (7H, m), 6.49 (2H, s), 3.85 (9H, s), 3.30 -3.92 (6H, m), 2.74-2.96 (2H, m), 2.52 (2H, s), 1.93-2.30 (8H, m), 1.47-1 50 (2H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3416, 2933, 1714, 1637, 1603.

Mass Spectrometric Analysis (FAB) m / e: 653 (M + H) ⁺ .

Elemental analysis (% based on C ₃₅ H ₃₈ N ₂ O ₆ Cl ₂ • O, 5H ₂ O)
Calculated: C 63.44, H 5.93, N 4.22, Cl 10.70.

 Found: C, 63.63; H, 6.20; N, 4.11; Cl, 10.26.

[Example 2b]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzo-yl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1, 4'-piperidine]
24 mg (0.62 mmol) of sodium borohydride are dissolved in 1 ml of ethanol. To the resulting solution was added a solution of 1- {2 [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-indanone) -1 , 4'-piperidine] (100 mg (0.16 mmol)) obtained in Example 2a in ethanol (1 ml) under ice-cooling, followed by stirring for 2 hours under nitrogen. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent is distilled off under vacuum. The residue was purified by flash chromatography on silica gel (solvent; methylene chloride: methanol = 10: 1) to obtain 80 mg (78%) of the title compound as white crystals.

[α] _D + 8.3 ^° (c = 0.52, chloroform).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm: 7.19-7.69 (7H, m), 6.50 (2H, s), 5.23 (1H, t, J = 5, 9 Hz), 3.85 (9H, s), 3.41-4.02 (6H, m), 2.78-2.89 (2H, m), 1.37-2.45 (12H, m )

IR absorption spectrum ν _max , cm ^-1 (KBr):
3424, 2928, 1634, 1584.

Mass Spectrometric Analysis (EI) m / e: 654 (M) ⁺ .

Elemental analysis (% based on C ₃₅ H ₄₀ N ₂ O ₆ Cl ₂ • 0.5H ₂ O)
Calculated: C 63.25, H 6.22, N 4.21, Cl 10.67.

 Found: C, 63.24; H, 6.35; N, 4.05; Cl, 10.22.

[Example 3]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [((2S) -hydroxy) indan-1, 4'-piperidine]
(Connection 138 described below)
300 mg (0.547 mmol) of 2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethanolmethanesulfonate, 144 mg (0.602 mmol) are suspended in 6 ml of dimethylacetamide. ) spiro [((2S) -hydroxy) indan-1,4'-piperidine] hydrochloride obtained in Reference Example 7, 138 mg (1.64 mmol) of sodium bicarbonate and 136 mg (0.821 mmol) of sodium iodide, followed by heating at 80 ^{° C.} for 8 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. The solvent is distilled off under vacuum. The residue was purified by silica gel column chromatography (silica gel; 15 g, eluent; hexane: ethyl acetate = 1: 1 -> 1: 3, methylene chloride: methanol = 50: 1 -> 20: 1) to obtain 297 mg (83% ) 1- {2 [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [((2S) -hydroxy) indan-1, 4'-piperidine] in the form of white crystals.

Melting point: 121 ^o C.

(с=0,96, хлороформ).

(c = 0.96, chloroform).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm: 7.67-7.16 (7H, m), 6.52 (2H, br s), 4.40 (1H, br s) 3.85 (9H, s), 4.04-3.37 (6H, m), 3.27 (1H, dd, J = 16.7 Hz, 5.3 Hz), 2.82 (1H, d, J = 16.7 Hz), 2.88-2.62 (2H, m), 2.40-1.49 (10H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3427, 2933, 1634, 1584, 1465, 1428, 1415, 1330, 1237, 1128.

Mass Spectrometric Analysis (FAB) m / e: 655 (M + H) ⁺ .

Elemental analysis (% based on C ₃₅ H ₄₀ Cl ₂ N ₂ O ₆ • H ₂ O)
Calculated: C 62.41, H 6.29, N 4.16, Cl 10.53.

 Found: C, 62.33; H, 6.27; N, 3.90; Cl, 10.49.

[Example 4]
1- {2 - [(2R) - (3,4-Dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [((2S) -hydroxy) indan-1, 4'-piperidine] (The following compound 138 hydrochloride).

 297 mg (0.453 mmol) of 1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} is dissolved in 3.0 ml of ethanol} the spiro [((2S) -hydroxy) indan-1,4'-piperidine) obtained in Example 3. To the resulting solution, 0.57 ml of a 4 N solution of hydrogen chloride in 1,4-dioxane was added with ice cooling, followed by stirring within 30 minutes Then, the solvent was evaporated under reduced pressure, the residue was washed with ether to obtain 304 mg (yield: 97%) 1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholine -2-yl] ethyl} spiro [((2S) -hydroxy) indan-1,4'-piperidine] hydrochloride as white crystals.

Melting point: 169 ^o C.

(с=1,0, метанол).

(c = 1.0, methanol).

Nuclear Magnetic Resonance Spectrum (400 MHz, DMCO-d ₆ ) δ, ppm: 10.78 (1H, m), 7.88-7.32 (3H, m), 7.27-7.06 (4H, m), 6.76-6.61 (2H, m), 4.93-4.92 (1H, m), 4.39-4.38 (1H, m), 3.81 (6H, s) 3.70 (3H, s), 4.22-2.58 (15H, m), 2.41-1.18 (4H, m), 1.69-1.48 (1H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3360, 2937, 2561, 1635, 1584, 1464, 1427, 1330, 1237, 1127.

Mass Spectrometric Analysis (FAB) m / e: 655 ([M + H] ⁺ ) free form).

Elemental analysis (% based on C ₃₅ H ₄₀ Cl ₂ N ₂ O ₆ • 1 / 2H ₂ O)
Calculated: C 59.96, H 5.89, N 4.00, Cl 15.17.

 Found: C, 59.94; H, 5.81; N, 3.94; Cl, 15.22.

 Compounds to be described below were synthesized in a similar manner as described in the above examples.

В данном случае в нижеописанной таблице, "Ас" обозначает ацетильную группу, "Me" обозначает метильную группу, "Ph" обозначает фенил, "iPr" обозначает изопропил и каждый заместитель (в таблице обозначенный как "зам") обозначает группу, представленную в табл.А.

In this case, in the table below, “Ac” refers to an acetyl group, “Me” refers to a methyl group, “Ph” refers to phenyl, “iPr” refers to isopropyl and each substituent (indicated in the table to “deputy”) refers to the group shown in Table .A.

 In the table. 1-3 compounds designated as Compounds 1-192 and Compounds 321-384 are preferred, of which compounds designated as Compounds 97-192 are more preferred, and compounds designated as Compounds 101-106, 133-138 and 165 -179 are even more preferred.

Most preferred are compounds:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [1H-indene-1,4'-piperidine] ,
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) 1H-indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) 1H-indan-1,4 ' piperidine] and
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [1H-inden-1,4'-piperidine],
particularly preferred compounds are:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine] and
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine].

[Reference examples]
The present invention will now be described with reference to Reference Examples.

[Reference example 1]
N-tert-butoxycarbonyl-spiro (1H-indene-1,4'-piperidine)
11.6 g (0.10 mol) of indene are dissolved in 60 ml of anhydrous tetrahydrofuran, followed by dropwise addition of 200 ml (0.20 mol) of lithium bis-tri-methylsilylamide (1.0 M tetrahydrofuran solution) for one hour under ice-cooling. . After 30 minutes stirring, 50 ml of a tetrahydrofuran solution of 24.2 g (0.10 mol) of N-tert-butoxycarbonyl-bis (2-chloroethyl) amine are added dropwise to the reaction mixture for 20 minutes. The resulting mixture was then stirred for 2 hours under ice cooling. The reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 97: 3) to obtain 21.3 g (89%) of the entitled compound as white crystals.

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl ₃ ) δ, ppm:
7.21-7.41 (4H, m), 6.85 (1H, d, J = 5.7 Hz), 6.79 (1H, d, J = 5.7 Hz), 4.11-4 28 (2H, m), 3.07-3.23 (2H, m), 2.01 (2H, dt, J = 12.8, 4.5 Hz), 1.51 (9H, s), 1.47-1.50 (2H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
2965, 1680, 1425, 1365, 1245, 1165.

Mass Spectrometric Analysis (EI) m / e: 285 (M) ⁺ .

[Reference example 2]
N-tert-butoxycarbonyl-spiro [(2-hydroxy) indan-1,4'-piperidine] and
N-tert-butoxycarbonyl-spiro [(3-hydroxy) indan-1,4'-piperidine]
In 100 ml of anhydrous tetrahydrofuran, 10.0 g (35.0 mmol) of N-tert-butoxycarbonyl-spiro (1H-indene-1,4'-piperidine), prepared as described in Reference Example 1, was dissolved, followed by dropping 52. 5 ml (52.5 mmol) of the tetrahydrofuranorane complex (1.0 M tetrahydrofuran solution) for 1.5 hours under ice-cooling. The resulting mixture was stirred for 30 minutes while cooling with ice and then for 4 hours at room temperature. Under ice cooling, ethanol was added to the reaction mixture. Then it is stirred for 5 minutes and 13 ml of a 6 N aqueous solution of sodium hydroxide are added dropwise to the reaction mixture for 20 minutes. Then 13.0 ml of a 30% aqueous solution of hydrogen peroxide are added dropwise in 25 minutes, followed by stirring for 20 minutes under ice-cooling and 3 hours at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over anhydrous sodium sulfate. Then the solvent is distilled off in vacuo. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7: 30-60: 40) to obtain 5.83 g (55%) of N-tert-butoxycarbonyl-spiro [(2-hydroxy) indan-1 , 4'-piperidine] as a non-polar substance and 4.20 g (40%) of N-tert-butoxycarbonyl-spiro [(3-hydroxy) indan-1,4'-piperidine] as a polar substance, each as white crystals.

N-tert-butoxycarbonyl-spiro [(2-hydroxy) indan-1,4'-piperidine]
Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl ₃ ) δ, ppm:
7.20-7.29 (4H, m), 4.48-4.52 (1H, m), 3.96 (2H, br s), 3.32 (1H, dd, J = 16.7 , 5.3 Hz), 3.24 (2H, m), 2.86 (1H, dd, J = 16.7, 1.0 Hz), 2.02-2.06 (1H, m), 1 84 (1H, m), 1.52-1.65 (3H, m), 1.49 (9H, s).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3620, 2980, 2935, 1680, 1430, 1365.

Mass Spectrometric Analysis (EI) m / e: 303 (M) ⁺ .

N-tert-butoxycarbonyl-spiro [(3-hydroxy) indan-1,4'-piperidine]
Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl ₃ ) δ, ppm:
7.42 (1H, d, J = 7.0 Hz), 7.26-7.36 (2H, m), 7.23 (1H, d, J = 7.0 Hz), 5.29 (1H d, J = 7.2 Hz), 4.12 (2H, m), 2.95 (1H, m), 2.53 (1H, q, J = 6.9 Hz), 1.9-1 98 (2H, m), 1.72-1.80 (2H, m), 1.61-1.67 (1H, m), 1.49 (9H, s), 1.38-1.42 (1H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3605, 2980, 2935, 1680, 1430, 1365.

Mass spectrometric analysis (EI) m / e: 303 (M) ⁺ .

[Reference example 3]
Spiro [(2-hydroxy) indan-1,4'-piperidine] hydrochloride
2.51 g (8.27 mmol) of N-tert-butoxycarbonyl-spiro [(2-hydroxy) indan-1,4'-piperidine], prepared as described in Reference Example 2, is dissolved in 10 ml of ethanol, then 10 is added. , 0 ml (40.0 mmol) of a 4 N solution of hydrochloric acid in dioxane for 5 minutes under ice-cooling. After this, the reaction mixture was stirred for 30 minutes while cooling with ice and 4 hours at room temperature. The solvent was removed in vacuo from the reaction mixture. The residue was recrystallized from methanol / diethyl ether to give 1.64 g (83%) of the title compound as white crystals.

Melting point: 250-251 ^o C.

Nuclear Magnetic Resonance Spectrum (400 MHz, DMCO-d ₆ ) δ, ppm:
8.99 (2H, m), 7.13-7.22 (4H, m), 5.19 (1H, s), 4.38 (1H, s), 3.13-3.26 (5H, m), 2.77 (1H, dd, J = 16.5, 3.2Hz), 2.07 (1H, d, J = 14.0 Hz), 1.82-1.99 (2H, m) 1.60 (d, J = 14.0 Hz).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3390, 2973, 2826, 1598.

Mass spectrometric analysis (EI) m / e: 203 (M) ⁺ (free form).

[Reference example 4]
N-tert-butoxycarbonyl-spiro [(3-indanone) -1,4'-piperidine]
2.00 g (6.59 mmol) of N-tert-butoxycarbonyl-spiro [(3-hydroxy) indan-1,4'-piperidine], prepared as described in Reference Example 2, are dissolved in 40 ml of methylene chloride. 12.0 g of powdered molecular sieves of 4 angstroms and 2.84 g (13.2 mmol) of pyridinium chlorochromate are added to the solution under ice-cooling, followed by 30 minutes of stirring. The mixture was then stirred for 2 hours at room temperature. Then 80 ml of diethyl ether are added to the reaction mixture, and the resulting mixture is filtered through Zeolite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent; n-hexane: ethyl acetate = 75:25) to obtain 1.98 g (99%) of the title compound as white crystals.

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm:
7.75 (1H, d, J = 8.0 Hz), 7.65 (1H, dd, J = 8.0, 8.0 Hz), 7.49 (1H, d, J = 8.0 Hz ), 7.42 (1H, dd, J = 8.0, 8.0 Hz), 4.23 (2H, br s), 2.86 (2H, m), 2.64 (2H, s) 1.99 (2H, dt, J = 13.2, 4.4 Hz), 1.50-1.53 (11H, m).

IR absorption spectrum ν _max , cm ^-1 (CHCl ₃ ):
2980, 2940, 1710, 1685, 1430.

Mass spectrometric analysis (EI) m / e: 301 (M) ⁺ .

[Reference example 5]
Spiro [(3-indanone) -1,4'-piperidine] hydrochloride
1.94 g (6.50 mmol) of N-tert-butoxycarbonyl-spiro [(3-indanone) -1,4'-piperidine], prepared as described in Reference Example 4, are dissolved in 20 ml of ethanol, then 17 are added dropwise. 0 ml (65.0 mmol) 4 N solution of hydrogen chloride in dioxane for 5 min under ice cooling. After this, the reaction mixture was stirred for 30 minutes while cooling with ice and 2 hours at room temperature. The solvent was removed in vacuo from the reaction mixture and the residue was recrystallized from methanol / diethyl ether to give 1.46 g (94%) of the title compound as white crystals. Melting point: 227-228 ^o C.

Nuclear Magnetic Resonance Spectrum (400 MHz, DMCO-d ₆ ) δ, ppm:
9.07 (2H, br s), 7.78 (1H, dd, J = 7.8, 7.8 Hz), 7.65 (1H, J = 7.8 Hz), 7.59 (1H d, J = 7.8 Hz), 7.50 (1H, dd, J = 7.8, 7.8 Hz), 3.34-3.37 (2H, m), 2.99-3, 37 (2H, m), 2.76 (2H, m), 2.27 (2H, dt, J = 13.8, 4.1 Hz), 1.64-1.68 (2H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3030, 2703, 2500, 1690, 1610, 1470.

Mass spectrometric analysis (EI) m / e: 201 (M) ⁺ (free form).

[Reference example 6]
N-tert-Butoxycarbonyl-spiro [((2S) -hydroxy) indan-1,4'-piperidine]
2.5 g of a tetrahydrofuran solution of 2.5 g are added to 0.42 ml (0.42 mmol) of a 1.0 M toluene solution of (R) -2-methyl-CBS-oxazaborolidine at a rate of 1.0 ml / min 8.30 mmol) N-tert-butoxycarbonyl-spiro [(2-indanone) -1,4'-piperidine] and 4.2 ml of a 1 M tetrahydrofuran solution of the borane-tetrahydrofuran complex. The resulting mixture was stirred for 1 hour at room temperature, then water was added under ice-cooling. After extracting the reaction mixture with ethyl acetate, the organic layer was washed with saturated NaCl and dried over anhydrous sodium sulfate. Then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain 2.51 g (yield: 100%, optical purity: 89% ee) N-tert-butoxycarbonyl-spiro [((2S) -hydroxy) indane -1,4'-piperidine] in the form of white crystals.

 The resulting crystals were dissolved in 5.0 ml of ethyl acetate while heating in a water bath. 150 ml of hexane are added and the resulting mixture is left to stand, 1.9 g of white crystals are obtained. The same procedure was repeated again and 1.52 g (yield: 61%, optical purity: 199% ee) of N-tert-butoxycarbonyl-spiro [((2S) -hydroxy) indan-1,4'-piperidine] in the form of white crystals.

 In this case, the optical purity of the title compound was determined by high performance liquid chromatography (HPLC) of a nitrobenzoyl derivative of the title compound, which was obtained as described in Reference Example 8.

Melting point: 106 ^o C.

(с=1,0, метанол).

(c = 1.0, methanol).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm:
7.28-7.18 (4H, m), 4.50 (1H, dd, J = 4.9.1.9 Hz), 4.07-3.83 (2H, m), 3.32 ( 1H, dd, J = 16.7 Hz, 4.9 Hz), 3.30-3.12 (2H, m), 2.86 (1H, dd, J = 16.7 Hz, 1.9 Hz) 2.08-1.99 (1H, m), 1.89-1.78 (1H, m), 1.49 (9H, s), 1.64-1.42 (2H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3349, 2934, 1698, 1425, 1367, 1168, 1162.

Mass Spectrometric Analysis (FAB) m / e: 304 (M + H) ⁺ .

Elemental analysis (% based on C ₁₈ H ₂₅ NO ₃ )
Calculated: C 71.26, H 8.31, N 4.62.

 Found: C, 70.99; H, 8.24; N, 4.68.

[Reference example 7]
Spiro [((2S) -hydroxy) indan-1,4'-piperidine] hydrochloride
1.5 g (4.95 mmol) of N-tert-butoxycarbonyl-spiro [((2S) -hydroxy) indan-1,4'-piperidine], prepared as described in Reference Example 6, are dissolved in 12.4 ml of ethanol. To the resulting solution, 6.2 ml of a 4 N solution of hydrogen chloride in 1,4-dioxane are added under ice-cooling, followed by 5 hours of stirring at room temperature. The solvent was removed in vacuo from the reaction mixture. The residue was washed with ether to give 1.1 g (yield: 93%) spiro [((2S) -hydroxy) indan-1,4'-piperidine] hydrochloride as white crystals.

Melting point: 247 ^o C.

(с=0,50, метанол).

(c = 0.50, methanol).

Nuclear Magnetic Resonance Spectrum (400 MHz / DMSO-d ₆ ) δ, ppm:
8.98 (2H, m), 7.22-7.17 (4H, m), 5.20 (1H, d, J = 5.0 Hz), 4.40-4.37 (1H, m) 3.26-3.13 (5H, m), 2.77 (1H, dd, J = 16.5, 3.2 Hz), 2.07 (1H, d, J = 14.0 Hz), 1.99-1.82 (2H, m), 1.60 (1H, d, J = 14.0 Hz).

IR absorption spectrum ν _max , cm ^-1 (KBr):
3413, 3269, 2937, 1607, 1431, 1074, 765.

Mass spectrometric analysis (EI) m / e: 203 (M) ⁺ (free form).

Elemental analysis (% based on C ₁₃ H ₁₇ NO • HCl)
Calculated: C 65.13, H 7.57, N 5.84, Cl 14.79.

 Found: C, 64.89; H, 7.48; N, 5.82; Cl, 15.01.

[Reference example 8]
N-tert-butoxycarbonyl-spiro [(2S) - (4-nitrobenzoyloxy) indan-1,4'-piperidine]
N-tert-Butoxycarbonyl-spiro [((2S) -hydroxy) indan-1,4'-piperidine, 30.3 mg (0.1 mmol), prepared as described in Reference Example 6, was dissolved in 2.0 ml methylene chloride. To the resulting solution was added 0.042 ml (0.3 mmol) of triethylamine, 1.2 mg (0.01 mmol) of 4-dimethylaminopyridine and 28 mg (0.15 mmol) of 4-nitrobenzoyl chloride, stirred at room temperature for 3 hours. The solvent was evaporated from the reaction mixture under vacuum. The residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to obtain 42 mg (yield: 93%, optical purity: 100% ee) N-tert-butoxycarbonyl-spiro [((2S) - ( 4-nitrobenzoyloxy) indan-1,4'-piperidine] in the form of white crystals The optical purity of the compound was determined by HPLC analysis.

Melting point: 75.6 ^o C.

(с=1,18, хлороформ).

(c = 1.18, chloroform).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl ₃ ) δ, ppm: 8.25 (2H, d, J = 8.9 Hz), 8.11 (2H, d, J = 8, 9 Hz), 7, 34-7.17 (4H, m), 5.83 (1H, d, J = 5.3 Hz), 4.11-3.84 (2H, m), 3.52 (1H, dd, J = 17.4 Hz, 5.3 Hz), 3.32-3.13 (1H, m), 3.04 (1H, d, J = 17.4 Hz), 3.02-2.92 (1H, m), 2.16-1.97 (2H, m), 1.73-1.58 (2H, m), 1.47 (9H, s).

IR absorption spectrum ν _max , cm ^-1 (KBr):
2975, 1723, 1695, 1530, 1279, 1167.

Mass Spectrometric Analysis (FAB) m / e: 452 [(M + H) ⁺ ].

Elemental analysis (% based on C ₂₅ H ₂₈ N ₂ O ₆ )
Calculated: C 66.36, H 6.24, N 6.19, O 21.21.

 Found: C, 66.33; H, 6.37; N, 5.95.

HPLC analysis
Column: Chiral Cel AD (manufactured by Daicel Chemical Industris, Ltd., inner diameter 4.6 mm, length 250 mm)
Eluent: hexane: 2-propanol = 50:50.

 Flow rate: 0.5 ml / min.

Temperature: 40 ^o C.

 Detection: 254 nm.

 Retention time: 17.1 minutes

[Reference example 9]
N-tert-butoxycarbonyl-spiro [((2R) -hydroxy) indan-1,4'-piperidine
Using a procedure similar to that described in Reference Example 6, from 0.5 g (1.66 mmol) of N-tert-butoxycarbonyl-spiro [(2-indanone) -1,4'-piperidine using 0.083 ml (0.083 mmol) 1 A 0 M toluene solution of (S) -2-methyl-CDS-oxazabrazine gives 215 mg (yield: 43%, optical purity: 100% ee) N-tert-butoxycarbonyl-spiro [((2R) -hydroxy) indan-1 , 4'-piperidine in the form of white crystals.

 (The optical purity of the above compound is determined by high performance liquid chromatography (HPLC) of a nitro-benzoyl derivative of the title compound, which was obtained as described in Reference Example 10).

 Melting point, nuclear magnetic resonance spectrum, IR absorption spectrum, spectrometric analysis of the target compound coincide with the (S) -form of the same compound obtained in Reference example 6.

(с=1,0, метанол).

(c = 1.0, methanol).

Elemental analysis (% based on C ₁₈ H ₂₅ NO ₃ )
Calculated: C 71.26, H 8.31, N 4.62.

 Found: C, 71.09; H, 8.25; N, 4.68.

[Reference example 10]
N-tert-butoxycarbonyl-spiro [((2R) - (4-nitrobenzoyloxy) indan-1,4'-piperidine
Using a procedure similar to that described in Reference example 9, 43 mg were obtained from 30.3 mg (0.1 mmol) of N-tert-butoxycarbonyl-spiro [(2R) -hydroxy) indan-1,4'-piperidine] (yield: 95%, optical purity: 100% ee) N-tert-butoxycarbonyl-spiro [(2R) - (4-nitrobenzoyloxy) indan-1,4'-piperidine] as white crystals. The optical purity of the compound was determined by HPLC analysis. The melting point, nuclear magnetic resonance spectrum, IR absorption spectrum, mass spectrometric analysis of the target compound coincide with the (S) -form of the same compound obtained in Reference example 8.

(с=0,76, хлороформ).

(c = 0.76, chloroform).

Elemental analysis (% based on C ₂₅ H ₂₈ N ₂ O ₆ • 1 / 4H ₂ O)
Calculated: C 65.70, H 6.29, N 6.13.

 Found: C, 65.97; H, 6.38; N, 6.01.

HPLC analysis
Column: Chiral Cel AD (manufactured by Daicel Chemical Industris, Ltd., inner diameter 4.6 mm, length 250 mm)
Eluent: hexane: 2-propanol = 50:50.

 Flow rate: 0.5 ml / min.

Temperature: 40 ^o C.

 Detection: 254 nm.

 Retention time: 10.1 minutes

[Reference example 11]
N-tert-butoxycarbonyl-spiro [((2R, 3S) -epoxy) indan-1,4'-piperidine]
N-tert-butoxycarbonyl-spiro [1H-indan-1,4'-piperidine], 100 mg (0.35 mmol) was dissolved in 2.0 ml of methylene chloride. To the resulting solution was added 11.4 mg (0.018 mmol) of (S, S) (+) - N, N'-bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediaminomanganese (III) chloride, and then 19 mg (0.11 mmol) of 4-phenylpyridinine-N-oxide. The resulting mixture was stirred for 10 minutes. Then, 1.1 ml (0.7 mmol) of a 1.0 M aqueous solution of sodium hypochlorite was added to the mixture, and the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and then dried with anhydrous sodium sulfate. The extract solvent was evaporated in vacuo. The residue was subjected to preparative thin layer chromatography (solvent, hexane: ethyl acetate = 2: 1) to obtain 53.6 mg (yield: 51%, optical purity: 91% ee) N-tert-butoxycarbonyl-spiro [((2R, 3S) - epoxy) indan-1,4'-pipepidine] as white crystals.

 The optical purity of the compound was determined by HPLC analysis.

Melting point: 149 ^o C.

(с=1, метанол, 99% ее).

(c = 1, methanol, 99% ee).

Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1 ₃ ) δ, ppm: 7.49 (1H, d, J = 7.3 Hz), 7.32-7.15 (3H, m), 4.28 (1H d, J = 2.9 Hz), 4.11 (1H, d, J = 2.9 Hz), 4.30-4.03 (2H, m), 3.15 (2H, br t, J = 12.0 Hz), 1.95-1.74 (3H, m), 1.51 (9H, s), 1.58-1.50 (1H, m).

IR absorption spectrum ν _max , cm ^-1 (KBr):
2949, 1679, 1424, 1365, 1244, 1168, 765.

Mass spectrometric analysis (EI) m / e: 301 (M ⁺ free form).

Elemental analysis (% based on C ₁₈ H ₂₃ NO ₃ )
Calculated: C 71.74, H 7.69, N 4.65.

 Found: C, 71.62; H, 7.67; N, 4.59.

HPLC analysis
Column: Chiral Cel AD (manufactured by Daicel Chemical Industris, Ltd., internal diameter 4.6 mm, length 250 mm).

 Eluent: hexane: 2-propanol = 80:20.

 Flow rate: 0.5 ml / min.

Temperature: 40 ^o C.

 Detection: 210 nm.

 Retention time: 13.2 minutes

[Reference example 12]
N-tert-Butoxycarbonyl-spiro [((2R, 3S) -hydroxy) indan-1,4'-piperidine]
125 mg (0.415 mmol) of N-tert-butoxycarbonyl-spiro [((2R, 3S) -epoxy) indan-1,4'-piperidine] are dissolved in 5.0 ml of 1,4-dioxane. To the resulting solution were added 151 mg (2.49 mmol) of ammonium formate and 10 mg of 5% palladium-on-charcoal and stirred at 80 ^{° C. for} 1 hour. 120 mg of ammonium formate and 10 mg of 5% palladium-on-charcoal are additionally added to the reaction mixture and stirred for 1 hour. Then the reaction mixture was left at room temperature and filtered. The filtrate solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain 118 mg (yield: 94%) N-tert-butoxycarbonylspiro [(2S) -hydroxy) indan-1,4'-piperidine] as white crystals.

 All the physical data of the entitled compound are the same as those for the compound of Reference Example 6.

[Reference example 13]
N-tert-butoxycarbonyl-spiro [((2R, 3S) -epoxy) indan-1,4'-piperidine]
Using 100 mg (0.35 mmol) of N-tert-butoxycarbonyl-spiro [1H-inden-1,4'-piperidine] and 11.4 mg (0.018 mmol) (R, R) (-) - N, N ' bis (3,5-di-tert-butylsalicylidene) -1,2-cyclohexanediamine-manganese (III) in the same manner as described in Reference example 11, 52.4 mg are obtained (yield: 50%, optical purity 87% of it) N-tert-butoxycarbonyl-spiro [((2S, 3R) -epoxy) indan-1,4'-piperidine] as white crystals.

 The optical purity of the compound was determined by HPLC analysis. Melting point, nuclear magnetic resonance spectrum, IR absorption spectrum, mass spectrometric analysis of the target compound coincide with the (2R, 3S) form of the same compound obtained in Reference Example 11.

(с=0,50, метанол, 99% ее).

(c = 0.50, methanol, 99% ee).

Elemental analysis (% based on C ₁₈ H ₂₃ NO ₃ • 1 / 3H ₂ O)
Calculated: C 70.33, H 7.76, N 4.56.

 Found: C, 72.22; H, 7.79; N, 4.53.

HPLC analysis
Column: Chiral Cel AD (manufactured by Daicel Chemical Industris, Ltd., internal diameter 4.6 mm, length 250 mm).

Eluent; hexane: 2-propanol = 80:20
Flow rate: 0.5 ml / min.

Temperature: 40 ^o C.

 Detection: 210 nm.

 Retention time: 10.9 min.

[Example composition]
A pharmaceutical composition comprising a compound (I) of the present invention or an ester or other derivative thereof as an active ingredient is prepared as follows:
[Example composition 1] Powder
The powder is prepared by mixing the compound of Example 1 (5 g), lactose (893 g) and corn starch in a mixer.

[Example composition 2] Granules
Preparation of granules: to a mixture of the compound of Example 2 (5 g), lactose (865 g) and unsubstituted hydroxypropyl cellulose (100 g) add 300 g of a 10% aqueous solution of hydroxypropyl cellulose, mix this mixture into a total mass, and granulate the plasticized mass in an extrusion granulator with subsequent drying of the granular product.

[Example composition 3] Capsules
Capsules are prepared by mixing the compound of Example 3 (5 g), lactose (115 g), corn starch (58 g) and magnesium stearate (2 g) in a V-shaped mixer, followed by filling the mixture with 180 mg capsules 3 in portions.

[Example composition 4] Tablets
Tablets are prepared by mixing the compound of Example 4 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) in a mixer and then tabletting the resulting mixture in a tablet machine.

[Test Example]
[Test Example 1] NK ₁ Receptor Binding Assay
(a) Preparation of samples of untreated pulmonary membranes
Samples of untreated pulmonary membranes were prepared from the lung of a male Harty guinea pig. Namely: they kill by bleeding from the abdominal aorta under chloroform anesthesia, followed by immediate excision of the lung and tissue of the respiratory tract.

 After perfusion of the excised lung with buffer (1) (50 mM Tris-HCl, pH 7.4), the lung is cut into thin slices and then homogenized in buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride ) using Polytron.

The tissue mass is removed from the homogenate, passing through a nylon mesh (50 nm), and separated by centrifugation (30000xg, 30 min, 4 ^o C). The precipitate was resuspended under ice-cooling in buffer (3) (buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and allowed to stand quietly for 60 min at 4 ^° C, the resulting suspension was centrifuged and washed twice (30000xg, 15 min, 4 ^o C).

Uncleaned membrane samples were stored at -80 ^° C until use.

(b) Receptor Binding Assay
250 μl of a solution of a sample of crude membranes is added to 250 μl of a mixed solution of the test drug and the [ ³ H] substance P (final concentration: 1 nM) (50 mM Tris-HCl, pH 7.4, 6 mM manganese chloride, 800 μg / ml BSA, 8 μg / ml hemostatin, 8 μg / ml leapeptin, 80 μg / ml bacitracin and 20 μg / ml phosphogramidone) and incubated for 30 min at room temperature.

 After the reaction, the membrane component is isolated on a GF / B glass filter (Whatman) using an automatic filtration system (Brandel).

 In this case, the glass filter is pretreated for about 4 hours with a 0.1% solution of polyethylene diamine to minimize non-specific binding.

The filtrate containing the membrane component is transferred to a miniplastic tube containing 4 ml Picoflow and measured
radioactivity with a liquid scintillation counter (Beckman, LCS3500).

[Test Example 2] NK ₂ Receptor Binding Assay
(a) Preparation of samples of untreated ileum membranes
Crude membrane samples were prepared from the ileum of a male Hartly guinea pig. Namely: they kill by bleeding from the abdominal aorta under chloroform anesthesia, followed by immediate excision of the ileum.

 The excised ileum is separated from the constituents, secrets and epithelium by scraping with a glass slide. Then it is cut into thin phases in buffer (1) (950 mM Tris-HCl, pH 7.4) and homogenized in buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride) using Polytron.

The tissue mass is removed from the homogenate, passing through a nylon mesh (50 μm) and separated by centrifugation (30000xg, 30 min, 4 ^o C). The precipitate was resuspended under ice-cooling in buffer (3) (buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and allowed to stand quietly for 60 min at 4 ^° C, the resulting suspension was centrifuged and washed twice (30000xg, 15 min, 4 ^o C).

Crude membrane samples were stored at -80 ^° C until use.

(b) Receptor Binding Assay
250 μl of the solution of the crude membrane sample is added to 250 μl of the mixed solution of the test drug and [ ³ H] -SR-48968 (Amercham, final concentration: 1 nM) (50 mM Tris-HCl, pH 7.4, 6 mM manganese chloride, 800 μg / ml BSA, 8 μg / ml hemostatin, 8 μg / ml leapeptin, 80 μg / ml bacitracin and 20 μg / ml phosphoramidone) and incubated for 30 minutes at room temperature.

 After the reaction, the membrane component is isolated on a GF / B glass filter (Whatman) using an automatic filtration system.

 In this case, the glass filter is pretreated for about 4 hours with a 0.1% solution of polyethylene diamine to minimize non-specific binding.

 The filtrate containing the membrane component was transferred to a mini-plastic tube containing 4 ml Picoflow, and radioactivity was measured by a liquid scintillation counter (Beckman, LSC3500).

 [Experiment 3] Inhibitory effect on increased vascular permeability.

The inhibitory effect on increased vascular permeability induced by the NK ₁ receptor antagonist, substance P (SP), is evaluated based on measuring the amount of leaked pigment obtained using conventional guinea pigs (male Hartley guinea pig weighing about 400 g). The increased vascular permeability was caused by the sequential administration of pigment (Evans blue: 20 mg / kg) to guinea pigs, anesthetized with pentobarbital (25 mg / kg, intraperitoneally), followed by immediate intravenous administration of SP (1 μg / kg). After 15 minutes, guinea pigs are killed under chloroform anesthesia and the amount of pigment leaked to the main areas of the respiratory tract is measured by the Harad method (J. Pharm. Pharmacol, 23, 218, (1971)). The test compound is suspended in a 0.5% tragacanth suspension and the resulting suspension is administered orally 1 hour before the introduction of SP. The inhibitory effect is determined by the amount of leaked pigment in guinea pigs, which was administered the test compound.

 [Test Example 4] Inhibitory effect on respiratory tract contraction.

The inhibitory effect of the test drug on the reduction of the respiratory tract caused by neurokinin A (NKA), which is an agonist of the NK ₂ receptor, is evaluated based on the internal pressure of the respiratory tract of conventional guinea pigs (male Hartley guinea pigs weighing about 500 g) in accordance with a modified method Konzet-Roessler (Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 71 (1940)).

 Namely: after implantation of the cannula of the respiratory tract with guinea pigs anesthetized with pentobarbital (30 mg / kg, ip) and administration of gallamine (20 mg / kg, intravenously), the animals are immediately breathed at a positive pressure of 8 ml / kg and 60 cycles / minute ( Ugo-Basile, 7025). The internal pressure of the respiratory tract during artificial respiration was increased by means of a pressure transducer (Nippon Danco, 200T) inserted into the canal of the lateral bronchus of the respiratory tract obtained (Nippon Denco, AP-601G) and recorded using an instrument (Nippon Denco WT-685G). To reduce the reduction of the respiratory tract 5 minutes after pretreatment with atropine (1 mg / kg, intravenously) and propanolol (1 mg / kg, intravenously), 4 μg / kg NKA is administered intravenously. Then, within 10 minutes, the internal pressure of the respiratory tract is measured. The test compound is prepared in a manner similar to that described in Test Example 3 and is administered orally one hour before the induction of NKA.

 Inhibitory activity is determined by comparing the area of internal pressure of the respiratory tract of the animal group to which the test compound was administered and the control group.

[Test Example 5] NK ₃ Receptor Binding Assay.

 (a) Preparation of samples of crude brain membranes.

Samples of untreated brain membranes are prepared from the brain of a male Hartley guinea pig. Specifically, the animals are killed by bleeding from the abdominal aorta under anesthesia with chloroform. After perfusion with buffer (1) (50 mM Tris-HCl, pH 7.4), the brain is immediately enucleated from the right ventricle. Dissected brains were homogenized with buffer (2) (buffer (1) containing 120 mM sodium chloride and 5 mM potassium chloride) using Polytron. The tissue mass is removed from the homogenate, passing through a nylon mesh (50 μm), and separated by centrifugation (30000xg, 30 min, 4 ^o C). The precipitate (membrane component) was resuspended under ice-cooling in buffer (3) (buffer (1) containing 10 mM EDTA and 300 mM potassium chloride) and allowed to stand quietly for 60 min at 4 ^o C, the resulting suspension was centrifuged and washed twice (30000xg, 15 min, 4 ^o C). To prepare a crude sample of membranes, the membrane components are suspended in buffer (1). It is stored at -80 ^° C until used in receptor binding assays.

 (b) Receptor binding assay.

The tube used in the reaction is pretreated with buffer (1) containing 5 mg / kg bovine serum albumin (BSA). To 100 μl of buffer (1) containing ... [ ³ H] -senctide, 6 mM manganese chloride, 800 μg / ml BSA, 8 μg / ml hemostatin, 8 μg / ml leapeptin, 80 μg / ml bacitracin and 20 μg / ml phosphoramidone, add 150 μg of buffer (1) containing 400 μg / ml BSA and test compound. In order to start the reaction, 250 μg / ml of a crude membrane sample was added to the resulting mixture (the protein concentration was adjusted to 1 mg / ml) (at the same time, the final concentration of [ ³ H] -senctide in the reaction medium was 2.5 nM).

 After incubation at room temperature for 60 minutes, the membrane component is isolated on a GF / B glass filter (Whatman) using an automatic filtration system (Brandel), which is pretreated with 0.1% polyethyleneimine for more than 4 hours, followed by washing three times with 5 ml of ice-cold buffer (4) (5 mM Tris-hydrochloric acid containing 400 μg / ml BSA and 0.01% sodium dodecyl sulfate, pH 7.4).

 The filtrate containing the membrane component was transferred to a miniplastic tube containing 4 ml Picoflow and the radioactivity was measured by a liquid scintillation counter (Aloka, LCS 3500).

In order to determine the radioactivity due to nonspecific binding of [ ³ H] -senctide (binding to sites other than the receptor, for example, a filter), the experiment is carried out with excess senctide (final concentration: 10 μM) and the radioactivity is measured.

The inhibition ratio of senctide receptor binding due to the test compound is calculated using the following equation:
Inhibition ratio (%) = [1- (CA) / (BA)] • 100
A: radioactivity due to non-specific binding
B: radioactivity in the test without the addition of the test compound
C: radioactivity in a test with the addition of a test compound
Compounds of the present invention that antagonize all NK ₁ , NK ₂ and NK ₃ receptors are superior in antagonistic activity to Compound A.

 Industrial applicability.

Since the spiro piperidine derivatives of this invention exhibit excellent antagonistic activity against NK ₁ , NK ₂ and NK ₃ receptors, have lower toxicity and excellent pharmacokinetics, they can be used as a medicine, especially for the prevention or treatment of asthma and / or bronchitis , rhinitis, allergies, or urinary incontinence.

Claims (12)

1. Derivatives of spiropiperidine represented by the formula (I)

where R ¹ represents a phenyl group, which may be optionally substituted with 1-3 substituents selected from halogen atoms, lower alkyl groups defined below, halogenated lower alkyl groups defined below, lower alkoxy groups defined below, lower alkoxycarbonyl groups including carbonyl groups substituted with a lower alkoxy group as defined below, hydroxyl groups, lower aliphatic acylamino groups including amino groups substituted with a lower aliphatic acyl group as defined below, and cya nogroups, or a 5- or 6-membered heterocyclic group containing from 1 to 3 atoms of oxygen, sulfur and / or nitrogen, which may optionally be fused to a phenyl group;
R ² represents a phenyl group which is substituted with 1-3 fluorine or chlorine atoms;
A represents a carbonyl group;
B represents a simple bond;
D represents an oxygen or sulfur atom;
E represents a C _1-4 alkylene group;

where G represents a C _5-8 cycloalkane ring which is substituted by a hydroxyl group;
Ar represents a phenyl ring; and
n represents an integer of 1 or 2;
or their pharmacologically acceptable salts; the lower alkyl groups indicated above represent straight or branched (C _1-6 ) alkyl groups; halogen-lower alkyl groups as defined above represent lower alkyl groups as defined above which are substituted by 1 or more halogen atoms; the lower alkoxy groups indicated above represent lower alkyl groups as defined above attached to an oxygen atom; the lower aliphatic acyl moiety of the lower aliphatic acylamino groups mentioned above is a C _2-7 aliphatic acyl group. 2. The compound of claim 1, wherein R ¹ is a phenyl group optionally substituted with 1-3 groups selected from lower alkyl groups, halogeno lower alkyl groups and lower alkoxy groups, as defined in claim 1, or a pharmacologically acceptable salt thereof .  3. The compound according to claim 1 or 2, where D represents an oxygen atom, or its pharmacologically acceptable salt. 4. The compound according to any one of paragraphs. 1-3, where E represents a C _2-3 alkylene group, or a pharmacologically acceptable salt thereof.  5. The compound according to any one of paragraphs. 1-4, where G is a cyclopentane ring substituted by a hydroxyl group, or a pharmacologically acceptable salt thereof.  6. The compound according to any one of paragraphs. 1-5, where n = 2, or its pharmacologically acceptable salt. 7. The compound according to claim 1, wherein R ¹ represents a phenyl group optionally substituted with 1-3 groups selected from lower alkyl groups, halogenated lower alkyl groups and lower alkoxy groups as defined in claim 1; R ² , A and B are as defined in paragraph 1; D represents an oxygen atom; E represents a C _2-3 alkylene group;

where G represents a cyclopentane ring substituted by a hydroxyl group; and n = 2; or a pharmacologically acceptable salt thereof. 8. The compound according to claim 1, selected from the group including the following compounds:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4'-piperidine ],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,5-dimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4'-piperidine ],
or their pharmacologically acceptable salts. 9. The compound according to claim 1, selected from the group including the following compounds:
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(2-hydroxy) indan-1,4 ' piperidine],
1- {2 - [(2R) - (3,4-dichlorophenyl) -4- (3,4,5-trimethoxybenzoyl) morpholin-2-yl] ethyl} spiro [(3-hydroxy) indan-1,4 ' piperidine],
or their pharmacologically acceptable salts. 10. The compound according to any one of paragraphs. 1-9 or a pharmacologically acceptable salt thereof as an active ingredient of a medicament for the prophylaxis or treatment of a disease that is treated or prevented by agents having antagonistic activity with respect to NK ₁ , NK ₂ and NK ₃ receptors. 11. A drug having an antagonistic effect on NK ₁ , NK ₂ and NK ₃ receptors, containing a pharmacologically effective ingredient and an excipient, characterized in that as a pharmacologically effective ingredient contains a compound according to any one of paragraphs. 1-9 or a pharmacologically acceptable salt thereof. 12. A method for the prevention or treatment of a disease that is treated or prevented by agents having an antagonistic effect on NK ₁ , NK ₂ and NK ₃ receptors, comprising administering to a warm-blooded animal an effective amount of a prophylactic or therapeutic agent, wherein said agent is a compound of any one of . 1-9 or a pharmacologically acceptable salt thereof.

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